One of the pathological hallmarks of Alzheimer's Disease is the presence of senile plaques containing beta-amyloid peptide (BAP). These plaques seem to be different from ordinary amyloid plaques in that they have microglia and astrocytes within and around the condensed core of the plaque. This observation prompted the hypothesis that microglia and astrocytes may play a crucial role in plaque formation and the pathology of Alzheimer's disease. Dr. Brunden has postulated that these glia have surface receptors for BAP and has put forth a theory of biochemical events which may lead to Alzheimer's Disease pathology. The theory goes something like this: Glia have substance P receptors. Microglia are the CNS equivalent of macrophages, and macrophages have a receptor called the serpin-enzyme complex (SEC) which binds both substance P and BAP. Thus, the PI postulates that glia have a SEC receptor or specific receptor for BAP. He further postulates that the BAP binding on glial surface receptors induces release of interleukin 1 (IL-1). The increased IL-1 could cause increased amyloid precursor protein (APP), of which BAP is a proteolytic bye product, and thereby advanced Alzheimer's Disease by increasing BAP even further. It is also postulated that IL-1 increases arachidonic acid and prostaglandin E2 (PGE2), thereby inducing glutamic acid uptake by astrocytes. This could result in excessive glutamate levels that would be excitotoxic and lead to neural cell death, thus promoting Alzheimer's Disease. As a preliminary data, the principal investigator has employed both a human glioblastoma cell line, U373 MG, and neonatal rat primary astrocetermine indirectly if these cells contains receptors that recognize both BAP and substance P (putative SEC receptors). Dr. Brunden found that 125I-substance P binds specifically to these glial cells. Using competitive binding assays he also showed that this binding was inhibited by the amino acid residues BAP (1-40) and BAP (25-35), but not by BAP (1-28). These results suggests that a SEC receptor may exist on glial cells. The proposed aims are: 1] to examine 125I-BAP (1-40) binding to microglia and astrocytes in culture for the presence of BAP receptors. Satchard analyses and competition studies will be used to demonstrate saturability, affinity and specificity of BAP binding. 2] to determine if BAP binding to receptors in astrocyte and microglia cultures increases IL-1 secretion. This will be assessed using a variation of the thymocyte costimulation bioassay which measures the proliferation of a certain T helper cell line that occurs after concanavalin A stimulation, only if exogenous IL-1 is present. 3] to determine if BAP binding induces the release of PGE2 from microglia, astrocytes or mixed glial cultures. The PGE2 will be measured using a commercial RIA kit. If the demonstration of the proposed "cascade" of cellular events is successful, the Phase II application would employ various inhibitors and antagonists (eg. to BAP, IL-1, PGE2 synthesis) to investigate possible mechanisms of halting of slowing the progress of Alzheimer's Disease.